This invention relates to a process for the manufacture of intermediates for .beta.-lactam antibiotics. In particular, it relates to an improved process for the manufacture of 7-substituted amino-3-exomethylenecepham ester sulfoxides.
The preparation of 3-exomethylenecepham sulfoxide esters is carried out by the known two-step process which comprises the conversion of a penicillin sulfoxide ester to a chlorosulfinylazetidinone followed by the cyclization of the latter to a 3-exomethylenecepham sulfoxide ester. The penicillin sulfoxide ester is converted to the intermediate chlorosulfinylazetidinone with an N-chloro halogenating agent as described by Kukolja in U.S. Pat. No. 4,165,315. The 4-chlorosulfinylazetidinone intermediates are described and claimed by Kukolja in U.S. Pat. No. 4,081,440. Chou, U.S. Pat. No. 4,075,203, describes the preparation of 3-exomethylenecepham sulfoxide ester via conversion of the penicillin sulfoxide ester in step 1 to the 4-chlorosulfinylazetidinone with an N-chloro halogenating agent in the presence of an alkylene oxide and calcium oxide. Later, Chou, U.S. Pat. No. 4,289,695, describes an improved process for 3-exomethylenecepham sulfoxide esters by employing an acid scavenging cross-linked polyvinylpyridine polymer in step 1.
Kukolja, U.S. Pat. No. 4,052,387, describes the cyclization of 4-chlorosulfinylazetidinones with a Lewis acid-type Friedel-Crafts catalyst, a Bronsted proton acid-type Friedel-Crafts catalyst or with a metathetic cation-forming agent. Subsequently, Chou, U.S. Pat. No. 4,190,724, describes and claims an improved process which comprises carrying out the Kukolja Friedel-Crafts catalyzed cyclization of a 4-chlorosulfinylazetidinone in the presence of oxo compounds such as ethers, ketones or phosphine oxides. Copp et al., U.S. Pat. No. 4,950,753, incorporated herein by reference, describes a further improvement of the Kukolja process which comprises carrying out the Friedel-Crafts cyclization in the presence of both an oxo compound of Chou and an unsaturated compound e.g., an alkene such as 1- or 2-hexene, a non-conjugated alkadiene such as 1,4-hexadiene, a cycloalkene such as cyclohexene, an allene, or a non-conjugated cycloalkadiene such as 1,4-cyclohexadiene. The present invention provides a further improvement of the Kukolja process which includes carrying out the Friedel-Crafts cyclization in the presence of a nitro compound, e.g., nitromethane, nitrobenzene, nitroethane, and nitrobenzene.